EGFR (epidermal growth factor receptor) is a receptor for cellular proliferation and signal transduction of epithelial growth factors (EGFs), and also known as HER1 or ErbB1. EGFR is one member of ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). EGFR is a type of glycoprotein, belongs to a tyrosine kinase receptor, has a trans-membrane and a molecular weight of 170 KDa.
EGFR is located on the surface of cell membrane, and is activated by binding to a ligand, including EGF and TGFα. The activated EGFR is converted into a dimer from a monomer. The dimer includes not only a combination of two homologous receptor molecules (homologous dimerization), but also a combination of different members of a human EGF-related receptor (HER) tyrosine kinase family (heterogeneous dimerization). The dimerized EGFR can activate its intracellular kinase pathway, including phosphorylation of key tyrosine residues in the intracellular domain, resulting in stimulation of many intracellular signal transduction pathways involved in the cellular proliferation and survival.
There is high expression or abnormal expression of EGFR in many solid tumors. EGFR is associated with tumor cell proliferation, angiogenesis, tumor invasion, metastasis, and apoptosis inhibition, and the possible mechanisms include: enhancement of downstream signal transduction caused by high expression of EGFR; continuous activation of EGFR caused by increased expression of a mutant EGFR receptor or ligand; enhancement of functions of an autocrine loop; destruction of down regulation mechanism of receptors; activation of an abnormal signal transduction pathway, and the like. Over-expression of EGFR plays an important role in the development of malignant tumors. The over-expression of EGFR has been found in tissues involving gliocyte, kidney cancer, lung cancer, prostate cancer, pancreatic cancer, and breast cancer.
Abnormal expression of EGFR and Erb-B2 plays a key role in the transformation and growth of tumors. Taking the lung cancer as an example, EGFR is expressed in 50% non-small cell lung cancer (NSCLC) cases, and its expression is associated with poor prognosis. The two factors enable EGFR and its family members to become major candidates for targeted therapy. Two small molecule inhibitors targeting EGFR, i.e., gefitinib and erbtinib, have been rapidly approved by the FDA for the treatment of patients with advanced NSCLC, who have lost response to conventional chemotherapy.
Early clinical data show that 10% NSCLC patients have response to gefitinib and erbtinib. Molecular biological analysis shows that in most cases, a patient having response to the drugs has a specific mutation on a gene encoding EGFR: deletion of amino acids 747 to 750 in exon 19 accounts for 45% mutations, and 10% mutations occur in exon 18 and exon 20. The most common EGFR activating mutations (L858R and delE746_A750) lead to increased affinity to the small molecule tyrosine kinase inhibitor (TKI) and decreased affinity to the adenosine triphosphate (ATP), as compared with the wild type (WT) EGFR. T790M mutation is a point mutation in exon 20 of EGFR, and is associated with acquired resistance to gefitinib or erbtinib. A latest research shows that the affinity of the combined L858R and T790M mutation to ATP is stronger than that of L858R only, and TKI is an ATP-competitive kinase inhibitor, thereby resulting in reduced binding rate between TKI and the kinase domain.
Because these mutations play an important role in the drug resistant mechanism of targeting EGFR therapy, it is necessary to provide an EGFR-L858R/T790M double mutation inhibitor for use in clinical treatment. Moreover, because inhibition of EGFR-WT will lead to many clinical toxic and side effects, it is also necessary to provide an inhibitor for use in clinical treatment, which has selectivity for EGFR-activating mutants (such as EGFR-L858R mutants, delE746_A750 mutants or EGFR exon 19 deletion mutants) or resistant EGFR mutants (e.g., EGFR-T790M mutants) as compared with EGFR-WT.
At present, a variety of selective EGFR inhibitors have been reported. WO2016070816 discloses an aniline pyrimidine compound of trifluoroethyl substituted indole:

Drug developers try to provide not only therapeutic efficacy, but also appropriate forms of active molecules having a property of forming a drug. Therefore, it is important for drug development to find a form having desired property.